The aim of the ESNATS project is to develop a novel "all-in-one" toxicity test platform based on embryonic stem cells (ESCs), in particular human ESC (hESCs), to accelerate drug development, reduce related R&D costs and propose a powerful alternative to animal tests in the spirit of the "Three R principle".
ESNATS addresses current shortcomings in drug toxicity testing:
- Testing takes place late in the development cycle, implying use of high numbers of animals and generating significant costs,
- Animal-based test systems bear the risk of non-prediction due to inter-species variation,
- In vitro assays rely on primary cells or cells lines of malignant origin that are hard to standardise and limited in regard to quantity, homogeneity and genetic diversity,
- Existing assay systems based on primary animal cell lines do not reliably represent the physiological situation of cells in native tissue.
To overcome these shortcomings, ESNATS will develop a novel testing system taking advantage of the unique potential of ESCs, including:
- their capacity to self renew, constituting an unlimited source of standardised cells,
- their pluripotency, providing a source for cells of different phenotypes required for toxicity testing,
- the physiological relevance of ESC-derived somatic cells for toxicity endpoints, guaranteeing high test predictivity,
- at least for murine ESC (mESC), their easy genetic manipulation, allowing use of reporter gene expression as a powerful toxicity testing tool.
To reach the project goals, a battery of toxicity tests will be developed using ESC lines subjected to standardised culture and differentiation protocols. Tests will cover embryoid bodies in several stages of development and differentiated derivatives including gamete and neuronal lineages, complemented with systems for hepatic metabolism. Genomics approaches will be used to determine predictive toxicogenomics signatures. The individual tests will be integrated into an "all-in-one" test system. To ensure later industrial usage, concepts for automated ESC culture will be developed and the test systems will be scaled up. In a later stage of the project, the predictivity, quality and reproducibility of the test strategy will be evaluated in a proof of concept study.
The results of ESNATS are expected to have an impact at several levels:
- on pharmaceutical R&D, by reducing costs for clinical trials as the number of unsuccessful candidate drugs are eliminated earlier in the testing process and productivity increases with better testing strategies;
- on public health, by contributing to the production of safer and cheaper drugs which will be available much quicker;
- on European stem cell research, by providing new technologies for stable hESC culture, improved protocols for hESC differentiation and a world leading toxicogenomic database.